Graham R Foster1, Kosh Agarwal2, Matthew E Cramp3, Sulleman Moreea4, Stephen Barclay5, Jane Collier6, Ashley S Brown7, Stephen D Ryder8, Andrew Ustianowski9, Daniel M Forton10, Ray Fox11, Fiona Gordon12, William M Rosenberg13, David J Mutimer14, Jiejun Du15, Christopher L Gilbert15, Ernest Asante-Appiah15, Janice Wahl15, Michael N Robertson15, Eliav Barr15, Barbara Haber15. 1. Queen Mary University, London, UK. 2. Institute of Liver Studies, Kings College Hospital, London, UK. 3. South West Liver Unit, Derriford Hospital and Peninsula Schools of Medicine and Dentistry, Plymouth, UK. 4. Bradford Teaching Hospitals Foundation Trust, Bradford, UK. 5. Glasgow Royal Campus, Glasgow, UK. 6. John Radcliffe Hospital, Oxford, UK. 7. Imperial College Healthcare NHS Trust, London, UK. 8. NIHR Biomedical Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospital NHS Trust and The University of Nottingham, Nottingham, UK. 9. North Manchester General Hospital, Manchester, UK. 10. St. Georges University of London, London, UK. 11. Gartnavel General Hospital, Glasgow, UK. 12. Hepatology Joint Clinical Research Unit, Bristol, UK. 13. Institute for Liver and Digestive Health, University College London, London, UK. 14. QE Hospital, Birmingham, UK. 15. Merck & Co., Inc., Kenilworth, NJ.
Abstract
Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).
RCT Entities:
Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).
Authors: Edward Tam; Julie Tremblay; Chris Fraser; Brian Conway; Alnoor Ramji; Sergio Borgia; Keith Tsoi; Eric M Yoshida; Bahe Rajendran; Gisela Macphail; Alexander Wong; Curtis Cooper; Keyur Patel; Marco Puglia; Kris Stewart; Benoit Trottier; Lucie Deshaies; Karen Doucette; Peter Ghali; Samuel S Lee; Jodi Halsey-Brandt; Janie B Trepanier Journal: Can Liver J Date: 2020-08-20
Authors: Elise J Smolders; Anouk M E Jansen; Peter G J Ter Horst; Jürgen Rockstroh; David J Back; David M Burger Journal: Clin Pharmacokinet Date: 2019-10 Impact factor: 6.447